PROJECT SUMMARY Iron deficiency anemia (IDA) experienced in early childhood causes long-lasting negative consequences on brain development, connectivity and cognition. Given the high prevalence of IDA in infants and toddlers and significant neurocognitive consequences, IDA screening is widely recommended in the first year of life. However, the brain continues to develop throughout childhood, and the incidence of IDA sharply increases again in late-childhood among menstruating females, occurring in 1 of every 16 adolescent females. Of greatest concern, recent studies have found that late-childhood IDA negatively impacts cognitive performance. Anemia results in cerebral metabolic stress with compensatory increases in cerebral blood flow and oxygen extraction fraction. In severe anemia, the compensatory mechanisms may be inadequate to maintain the expected metabolic rate of oxygen utilization (CMRO2), impacting the structural and functional development of the brain. The goal of this proposal is to delineate the short and long-term neurocognitive impact of late-childhood IDA in young females by testing the central hypothesis that late-childhood IDA causes cerebral metabolic stress that contributes to both reversible and potentially irreversible changes in neurocognitive function. Eighty-eight young females between 12-21 years of age with IDA will undergo cognitive evaluation and brain MRI assessing cerebral metabolism and structural and functional connectivity at time of diagnosis, 6 weeks after iron repletion, and at 1-year post-enrollment. Forty-four age-matched females without anemia will be enrolled and assessed at similar time-points for comparison. We will compare cerebral metabolic stress and compromised metabolism between the two groups (Aim 1). A subgroup of females with IDA that receive IV iron therapy will have brain MRIs weekly for 6 weeks post-repletion. Dense imaging of this subgroup will determine the hemoglobin threshold resulting in metabolic failure. The change in functional connectivity and cognitive abilities with resolution of anemia secondary to iron therapy will be measured to assess the potential reversibility of neurocognitive dysfunction with iron repletion (Aim 2). Lastly, cognitive evaluation and brain MRIs one year after enrollment will be used to determine the relationship between cerebral metabolic stress at diagnosis of IDA and long-term integrity of the white matter microstructure as it relates to cognitive abilities (Aim 3). Determining the neurocognitive effects of late-childhood IDA has important implications for potential screening and optimizing therapy recommendations at a time when cognitive performance has life-long implications for educational and career options for young women entering adulthood.